Concomitant cryoballoon ablation and percutaneous closure of left atrial appendage in patients with atrial fibrillation

EP Europace, Nov 2016

Fassini, Gaetano, Conti, Sergio, Moltrasio, Massimo, Maltagliati, Anna, Tundo, Fabrizio, Riva, Stefania, Dello Russo, Antonio, Casella, Michela, Majocchi, Benedetta, Zucchetti, Martina, et al.

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Concomitant cryoballoon ablation and percutaneous closure of left atrial appendage in patients with atrial fibrillation

Europace Concomitant cryoballoon ablation and percutaneous closure of left atrial appendage in patients with atrial fibrillation Gaetano Fassini 1 Sergio Conti 1 Massimo Moltrasio 1 Anna Maltagliati 0 Fabrizio Tundo 1 Stefania Riva 1 Antonio Dello Russo 1 Michela Casella 1 Benedetta Majocchi 1 Martina Zucchetti 1 Eleonora Russo 1 Vittoria Marino 1 Mauro Pepi 0 Claudio Tondo 1 0 Imaging Department, Centro Cardiologico Monzino, IRCCS , Via Parea 4, Milan 20138 , Italy 1 Cardiac Arrhythmia Research Centre, Department of Cardiovascular Sciences, University of Milan, Centro Cardiologico Monzino, IRCCS , Via Parea 4, Milan 20138 , Italy Aims Pulmonary veins (PVs) isolation is the cornerstone of atrial fibrillation (AF) ablation and can be achieved either by conventional radiofrequency ablation or by cryoenergy. Left atrial appendage (LAA) closure has been proposed as alternative treatment to vitamin K antagonists (VKA). We aimed to evaluate the feasibility of combining cryoballoon (CB) ablation and LAA occlusion in patients with AF and a high thromboembolic risk or contraindication to antithrombotic therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods Thirty-five patients (28 males, 74 + 2 years) underwent CB ablation. Left atrial appendage occlusion was carried out by and results using two occluder devices (Amplatz Cardiac Plug, ACP, St. Jude Medical, MN, USA, in 25 patients; Watchman, Boston Scientific, MA, USA, in 10 patients). Thirty patients (86%) had previous stroke/TIA episodes, 6 patients (17%) had major bleeding while on VKA therapy, and 7 patients (20%) had inherited bleeding disorders. Over the follow-up (24 + 12 months), atrial arrhythmias recurred in 10 (28%) patients. Thirty patients (86%) had complete sealing; 5 patients (14%) showed a residual flow (,5 mm) at first transoesophageal echocardiography (TEE) check, while at 1-year TEE residual flow was detected in 3 patients. In 13 patients (37%), VKA therapy was immediately discontinued. Six patients (17%) received novel oral anticoagulants treatment and then discontinued 3 months thereafter. No device-related complications or clinical thromboembolic events occurred. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Combined CB ablation and LAA closure using different devices appears to be feasible in patients with non-valvular AF associated with high risk of stroke or contraindication to antithrombotic treatment. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Introduction Pulmonary vein isolation (PVI) is regarded as the cornerstone to treat atrial fibrillation (AF) by means of transcatheter ablation.1,2 This target can be achieved by conventional point-to-point radiofrequency current delivery or by using cryoenergy through a specific balloon-designed platform. Furthermore, AF is the most challenging arrhythmia to treat in the general population, due to the unsatisfactory efficacy provided by antiarrhythmic drug therapy and the high risk of thromboembolic event.3,4 It is reported that the overall annual risk of stroke is 5% in patients suffering from AF and up to 15% in very high-risk patients.5 Left atrial appendage (LAA) is undoubtedly the main source of thrombus formation in patients with non-valvular AF.3 According to the International Guidelines, anticoagulation treatment needs to be prescribed to patients with CHA2DS2-VASc score ≥ 1 as to prevent embolic events.6 In the clinical practice, the administration of vitamin K antagonists (VKA) or novel oral anticoagulants (NOACs) can carry some critical disadvantages, such as profuse and frequent bleedings, no compliance, difficulty to keep a therapeutic range, and frequent interactions with some dietary components and medications,7 – 9 leading to patients undertreatment. What’s new? † Currently, we are not aware of other studies that have dealt with the concomitant cryoballoon (CB) ablation and left atrial appendage (LAA) closure. † It might be interesting to evaluate the safety and feasibility of a combined CB ablation and LAA closure using different occluding devices. † Our study shows that a combined CB ablation and LAA closure procedure seems to be safe and feasible in patients with non-valvular AF associated with high risk of stroke or contraindication to anticoagulation therapy. Due to the role of LAA in harbouring thrombi, an effective alternative to anticoagulation treatment is its mechanical occlusion.10,11 The percutaneous obliteration of LAA, using different device designs, has been shown to be successful both in a randomized clinical trial12,13 and in prospective and registry studies.14,15 Since patients with drug-resistant non-valvular AF may have high thromboembolic and/ or bleeding risks as well, we considered the combination of CB AF ablation and LAA mechanical closure as a valuable treatment strategy. The rationale of this single-center, observational study was to evaluate the feasibility and efficacy of the combined approach in patients who share indication to AF ablation and LAA closure, the latter due to both high risk of bleeding, previous history of thromboembolic, or major bleeding events during therapeutic anticoagulation treatment. In this study, we present the feasibility of this novel combined approach. Methods Patients population Patients with documented, drug-resistant, non-valvular paroxysmal or early persistent AF (≤12 months) who suffered thromboembolic events despite appropriate anticoagulation therapy or with a previous history of major bleedings on therapeutic anticoagulation were considered suitable for this treatment. For each patient, the CHA2DS2-VASc and the HAS-BLED scores were calculated. To rule out the presence of left atrial (LA) and LAA thrombi, all patients underwent twodimensional (2D) transoesophageal echocardiography (TEE) the day before the procedure, along with a transthoracic echocardiogram for the assessment of LA dimension, left ventricular ejection fraction (LVEF), and valvular function. In the majority of patients, a preprocedural computed tomography scan or magnetic resonance imaging was performed in order to assess LA anatomy and LAA dimension and morphology. Class Ic antiarrhythmic drugs were discontinued prior to ablation. Exclusion criteria were the occurrence of LA thrombus, LVEF ≤30%, contraindication to general anaesthesia and very enlarged LA dimension (≥55 mm or volume ≥30 mL). Since the concomitant AF catheter ablation and mechanical closure of LAA are not included in the International Guidelines,8 each patient was fully informed of the procedure and given a written consent form. The study protocol was approved by the local ethics committee. Procedure Cryoballoon ablation All procedures were carried out under general anaesthesia. Briefly, through a single transseptal puncture, a 28 mm cryoballoon (CB, Arctic Front, Medtronic, MN, USA, for the first 10 patients; Arctic Front Advance, Medtronic, MN, USA, for the remaining 25 patients) was inserted through a steerable dedicated sheath (FlexCath, Medtronic, MN, USA) in the LA. Once inflated and wedged in the pulmonary vein (PV) ostium, contrast dye was injected and PV occlusion was judged visually by the operator as to achieve a perfect occlusion as much as possible. According to the manufacturer’s recommendations, a 300 s freeze was delivered using the first-generation CB, reduced to 240 s in patients treated with the second-generation CB. Based on the time to PVI, temperature nadir reached and grade of PVs occlusion a bonus freeze was provided. The procedure was carried out under oesophageal temperature monitoring (Esotherm Plus, Fiab). Pulmonary vein activity recording during cryoenergy delivering was also attempted by positioning the Achieve catheter as close as possible to the distal portion of the CB as to determine time to PVI or the occurrence of electrical vein dissociation. Pulmonary vein isolation was then confirmed by repositioning the Achieve catheter to the most proximal site of the ostium; in all cases, bidirectional block along the PV – LA junction was assessed by the conventional pacing manoeuvres. For cryoenergy applications at the septal veins, pacing of the ipsilateral phrenic nerve with a 1000 ms cycle length at the maximum output (12 V @ 2.9 ms) was provided as to avoid phrenic nerve palsy. During the entire procedure, activated clotting time was maintained between 300 and 350 s. In the case of acute PV reconnection, adenosine was infused to investigate the durability of PVI after 20 – 30 min following ablation in that PV. Left atrial appendage closure The Amplatz Cardiac Plug (ACP) device (St. Jude Medical, MN, USA) first (n ¼ 2) and second releases (n ¼ 23) or the Watchman device (Watchman, Boston Scientific, MA, USA) was implanted (ACP device in 71% of patients, n ¼ 25, and Watchman device in 29% of patients, n ¼ 10) right after the ablation procedure was completed, while the patients were under general anaesthesia. According to the recently published EHRA/ EAPCI expert consensus statement on catheter-based LAA occlusion, we avoided to implant a Watchman device if the LAA length was less than the device diameter, or if the LAA diameter was ,17 or .30 mm. Differently, an ACP device was chosen if the landing zone diameter was ,29 mm (31 for Amulet), or if the LAA length was .10 mm (7.5 for Amulet). Thus, if the LAA anatomy and measurements, previously evaluated with a baseline TEE, allowed the use of both devices, the choice was taken according to the best therapeutic strategy for each patient. The implant was performed under monoplane fluoroscopy and 2D- and 3D-TEE guidance. The FlexCath steerable sheath previously used for CB ablation was replaced by a 14F long sheath for the ACP device and 14F sheath for the Watchman device and manoeuvred towards the ostium of the LAA. Throughout these sheaths, LAA angiograms for determining size and shape were performed. For the positioning of each device, a size 10–25% larger than the largest diameter of the LAA body (based on the measurements by both angiography and TEE) was preferred as to promote an effective compression for device stability. For both devices, before the releasing process, specific criteria had to be fulfilled, including no or minimal (,3 mm) residual lateral flow, absence of mitral valve leaflet interference (ACP cases), correct device position in relation to the circumflex artery plane, and confirmed device stability at the tug test. Once released, the position of the device was confirmed by TEE and angiography. Post-procedural management and follow-up Patients were discharged 48 h following the procedure, once a TTE and a fluoroscopy check confirmed the stable position of the LAA occluder device and the lack of any sign of pericardial effusion. All patients underwent anticoagulation therapy (VKA or NOACs) for at least 2 months after PVI.8 In addition, we adopted the recommendation on the base of device implanted (Figures 1 and 2). Briefly, after Watchman implantation, aspirin and warfarin for 6 weeks, followed by aspirin and clopidogrel for 6 months and aspirin lifelong. PVI + LAA closure ACP 2 months anticoagulation (VKA, NOAC, LMWH) or in the case of absolute contraindication aspirin and clopidogrel for 1 month aspirin for at least 3 months Conversely, after ACP implantation, clopidogrel for at least 1 month in the case of absolute contraindication to anticoagulation therapy and aspirin for at least 3 months were prescribed. Each patient, except those with inherited bleeding disorders (n ¼ 7, 20%), was assigned to VKA or NOAC therapy 24 h after the procedure, preceded by low-molecular-weight heparin (LMWH) bridging therapy started on the same day of the procedure. Therefore, the LMWH therapy was discontinued as soon as the target international normalized ratio (INR) of 2.0 – 3.0 was reached in those patients in whom VKA was chosen. Novel oral anticoagulants were considered in the case of labile INR or based on physician’s preference. Patients were followed up in the outpatient clinic 3 months after the procedure and every 3 months thereafter. At each visit, a standard 12-lead electrocardiogram (ECG) was obtained in all patients. Clinical events occurring during the follow-up and documentation of the events were carefully checked. All patients were followed up with ECG Holter monitoring at 6 and 12 months after CB ablation. Antiarrhythmic drugs were administered for the first 3 months and then tapered over based on the clinical course and patient’s preference. Moreover, between 30 and 60 days, according to device type, each patient underwent a TEE investigation to evaluate the proper position of the LAA device, and to rule out any thrombus and residual leakage. If the sealing criteria were confirmed, anticoagulation or double antiplatelet therapy was modified based on the guidelines recommendations. Transoesophageal echocardiography was repeated at 6 months and 1-year follow-up. Statistical analysis This was an observational, prospective, single-centre study. Patients’ clinical characteristics are reported as descriptive statistics. Continuous variables with normal distribution are reported as mean + standard deviation. Categorical variables are expressed as percentage. A P-value of ,0.05 was considered statistically significant. All statistical tests were performed using SPSS for Windows 17.0 (SPSS, Chicago, IL, USA). Results Thirty-five patients (mean age 72 + 4 years) were included in the study. The clinical characteristics are reported in Table 1. Twentyeight patients (80%) had paroxysmal AF and seven patients (20%) early persistent AF (≤12 months duration). The median CHA2DS2VASc score was 3, and the HAS-BLED score was 3. Seven patients (20%) had well-established inherited bleeding disorders (three patients with von Willebrand type 2 disease and the remaining four patients with type B haemophilia). Thirty patients (86%) had a previous stroke, 26 patients despite appropriate anticoagulation therapy. Besides the seven patients with inherited bleeding disorders, contraindication to continuous VKA therapy was ascertained in additional six patients. In these patients, intracranial bleeding (n ¼ 2) or profuse intestinal haemorrhage (n ¼ 4) prevented to re-establish therapeutic regimen of anticoagulation. Furthermore, 23% of patients (n ¼ 8, 3 among those with inherited bleeding disorders and 5 among those major gastrointestinal bleeding) had both major bleeding and cerebral ischaemic events (transient ischaemic attack). Procedural parameters Procedural parameters are reported in Table 2. The whole mean procedural time was 114 + 32 min for CB ablation and 44 + 12 min for LAA occlusion. Therefore, the overall procedural time was 165 + 34 min. The fluoroscopic time for the CB ablation procedure was 24 + 11 min and 9 + 3 min for LAA occlusion. The entire procedure was performed under general anaesthesia. Cryoballoon ablation In 35 patients, a total number of 132 PVs were identified, including a left common PV in 8 patients. In all cases, the 28 mm CB was used (first-generation CB n ¼ 10, second-generation CB n ¼ 25). Complete PVI was achieved in 34 out of the 35 patients (97%). In one patient, treated with the first-generation CB, the right inferior PV was not successfully occluded and, therefore, PVI was then achieved through radiofrequency applications. The average number of balloon applications per patients to achieve PVI was 8.75. Specific CB procedure-related complications occurred in two patients with transient phrenic nerve palsy, while ablating at the right superior PV. The nadir of temperature at that vein was below 2558C in both cases. Complete resolution of the phrenic nerve injury was demonstrated in both patients by Days 24 and 60, respectively. Pulmonary vein isolation was then checked on between 20 and 30 min after ablation. Acute reconnection was demonstrated in 5 veins (4%) (2 left common PVs and 3 at the inferior margin of the LIPV). In four of these veins, the first-generation CB was used. Left atrial appendage occlusion Occluder devices for LAA were implanted under fluoroscopy and TEE guidance right after the PVI was concluded. Once the size and shape of the LAA were determined by performing selected angiograms and TEE measurements, the chosen device (ACP or Follow-up Arrhythmia recurrence At a mean follow-up of 24 + 12 months, atrial arrhythmias (defined as AF or atrial flutter/atrial tachycardia) occurred in 29% of patients (n ¼ 10); 50% of them underwent a redo procedure, 3 patients developed persistent AF and refused to undergo an additional ablation; the remaining 2 patients were successfully managed with antiarrhythmic drugs. The redo ablation procedures were guided by EnSite NavX mapping system: PV – LA reconnection of at least one PV was detected in all patients (Table 3). Table 3 Follow-up Patients (n 5 35) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Months, mean + SD 24 + 12 Arrhythmia recurrence, n (%) 10/35 (29%) Redo ablation, n (%) 5/35 (14%) TEE evaluation, n (%) First TEE, complete sealing 30/35 (86%) First TEE, minimal leaking (,5 mm) 5/35 (14%) 12 months TEE, complete sealing 32/35 (91%) Stroke/TIA, n (%) 0/35 (0%) Device embolization/device thrombus, n (%) 0/35 (0%) VKA off, n (%) 30/35 (86%) Death, n (%) 0/35 (0%) TEE, transoesophageal echocardiography; TIA, transient ischaemic attack; VKA, vitamin K antagonists. Left atrial appendage closure In each patient, TEE evaluation was established between at 1, 6, and 12 months. Thirty patients (86%) had complete sealing, while the remaining 5 patients (14%) showed a persistent minimal residual flow (between 2 and 4 mm) at 180 days; the further check at 1 year revealed persistent residual flow in 3 patients. In no instances, device embolization or thrombus formation on surface device was detected. More importantly, no thromboembolic events had occurred. In particular, the expected a priori stroke rate was ≈4%/ year, whereas the observed 2-year rate was 0%. However, the risk reduction was not statistically significant, because in a sample of 35 subjects, an observed 2-year rate of 0% is compatible with a baseline risk ranging from 0 to ≈5%/year. Post-procedural anticoagulation management In 13 patients with major contraindication to anticoagulation therapy (37%; those who were known having inherited bleeding disorders and previous cerebral and profuse gastrointestinal haemorrhage), subcutaneous LMWH was administered for 2 months, followed by single antiplatelet therapy. Among the remaining patients, anticoagulation strategy followed the main recommendations with the exception of 6 patients (17%) who received NOAC treatment for the first 3 months (dabigatran in 4 patients and rivaroxaban in 2 patients, respectively). Discussion We reported a study of combined CB ablation of AF and LAA closure in a population of patients with non-valvular AF and a high risk of stroke or strong contraindication to anticoagulant treatment. The findings of the study confirm the feasibility of such an approach and indicate that it can be proposed as an effective alternative treatment to a very selected category of patients. Swaans et al.15 first published clinical results on LAA occlusion in combination with AF ablation in a single procedure. Recently, Calvo et al.16 reported the feasibility of this combined approach using radiofrequency energy delivery and Watchman or ACP devices. Even if our experience confirms the feasibility of the approach, there are differences between our experience and these studies. First, in our study, CB ablation was elected as privileged energy source to achieve PVI. Based on experimental data, we hypothesized that the potential injury (i.e. endothelial disruption, thrombus formation)17 of the tissue at the ridge between the left superior PV and the LAA, and around the LAA itself, could be lower using cryoenergy compared with conventional radiofrequency energy. According to the latest AF ablation guidelines, CB ablation is regarded as an alternative to radiofrequency when aiming at PVI. Finally, as well as in the study of Calvo et al., two different types of LAA occluder were used in our study, confirming the effectiveness of the procedure regardless of the design of the device. Differently, the whole safety profile of our approach was uneventful regarding major complications. Successful PVI with CB was achieved in all patients but one, confirming the high success rate of the approach. It is critical to highlight the fact that in this patient, failure of PVI was limited only to the right inferior PV when using the first-generation CB. Interestingly, the revised design of the second-generation CB as well as the dedicated sheath allowed a further increase of the acute success of PVI.18 Five out of 10 patients who had arrhythmia recurrences underwent a redo procedure: careful electroanatomical mapping by EnSite Navx provided demonstration of LA– PV reconnection of at least 1 PV in all patients (mean number per patient: 1.3 + 0.4). Interestingly, 4 out of 5 patients were treated with the first-generation CB during the index procedure. At a mean follow-up of 24 + 12 months, the success rate of a single procedure was 71%; while including the redo ablation, the overall success rate reached 84%. In this study, successful implantation of LAA occluder device was achieved in all patients, regardless of the device used. This confirms the high success rate of the procedure already reported in previous study.19 Complete sealing was accomplished in a high percentage of patients (86%, increased to 92% at 1-year TEE check); only in 3 patients a residual flow (,5 mm) persisted over time. Even the persistence of minimal, residual flow is not considered predictor of potential thromboembolic events,20 and longer TEE follow-up may be considered in patients who present this finding. In our population, no thromboembolic events were reported over the entire follow-up, suggesting that LAA occlusion and reduced probability to have arrhythmia recurrences after ablation, may constitute a valid option of treatment considering the particularly high risk of embolic events as well as the high predisposition to bleeding. It could be argued that combining ablation with LAA mechanical occlusion may bear some disadvantages, such as the need to keep the patient on anticoagulation for at least 2 – 3 months after the procedure. Although an interesting simplified anticoagulation protocol has been proposed after PVI by Duytschaever et al.,21 unfortunately we cannot adopt this strategy due to the high thromboembolic risk of the population enrolled in our study. However, in our preliminary experience, no haemorrhagic events were observed, even in those patients presenting with haemorrhagic tendency due to inherited bleeding diseases. Moreover, in this subpopulation, in which antithrombotic treatment for AF can be a challenge, even the NOAC drugs, at least non-inferior to VKA with a lower rate of intracranial bleeding as the most significant benefit, may bear the same bleeding risk. Also, we need to highlight the concept that patients with prior severe bleeding complications during VKA therapy or at high risk of bleeding do not represent an attractive population to be treated with NOACs. Since the longterm success rate of catheter ablation seems to be around 50 – 60% following single procedure,22 thus implying the need for anticoagulation therapy continuation, the combined procedure may result particularly helpful in some specific setting of patients deemed to undergo AF ablation: (a) patients with non-valvular AF and prior ischaemic event and (b) patients with clear contraindication to VKA therapy. Finally, considering the incidence of major complications related to AF ablation and LAA percutaneous closure which share the same procedural steps (vascular access, anticoagulation, transseptal puncture), the combination of PVI with LAA closure in a single step reduces the risks associated to a repeated LA procedure.19,23 Study limitations We acknowledge some limitations of our study. The number of patients is quite limited and prevented any final conclusion on safety due to the fact that the study is a non-randomized report. The main scope of the study was the feasibility of the approach, and we did not compare this strategy with AF ablation and LAA occlusion performed in two separate steps. At the end of the follow-up period, antithrombotic was not discontinued in all patients. This was due to the fact that in some patients, the referred cardiologists were the primary treating physicians and felt to keep patients on antithrombotic treatment, despite good TEE results. Holter recording was used in fixed time frame over the follow-up, and this might have limited the chance to detect asymptomatic AF episodes, favouring overestimation of the success rate of ablation. Furthermore, we neither did carry out cost-effectiveness evaluation of the combined strategy. Conclusion Combined CB ablation of PV and LAA mechanical closure appears to be feasible in patients with non-valvular AF associated with high risk of stroke or specific contraindication to antithrombotic treatment (VKA/NOACs). For the time being, this approach needs to be limited to specific and well-selected patients while randomized clinical trials are warranted as to define the benefit and costeffectiveness of this interventional strategy. Funding C.T. received throughout the 2015 consulting fees/honoraria not directly related to the LAA closure procedure using the Amplatzer device. Conflict of interest: G.F. and M.M. received consulting fees/honoraria from Medtronic, Inc. C.T. received consulting fees/honoraria from St. Jude Medical; Medtronic, Inc.; and Boston Scientific Corp. 1. Wazni OM , Marrouche NF , Martin DO , Verma A , Bhargava M , Saliba W et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial . JAMA 2005 ; 293 : 2634 - 40 . 2. Mohanty S , Mohanty P , Di Biase L , Bai R , Santangeli P , Casella M et al. 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Viles-Gonzalez JF , Kar S , Douglas P , Dukkipati S , Feldman T , Horton R et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation) substudy . J Am Coll Cardiol 2012 ; 59 : 923 - 9 . 21. Duytschaever M , Berte B , Acena M , De Meyer G , Bun SS , Van Heuverswyn F et al. Catheter ablation of atrial fibrillation in patients at low thrombo-embolic risk: efficacy and safety of a simplified periprocedural anticoagulation strategy . J Cardiovasc Electrophysiol 2013 ; 24 : 855 - 60 . 22. Weerasooriya R , Khairy P , Litalien J , Macle L , Hocini M , Sacher F et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011 ; 57 : 160 - 6 . 23. Cappato R , Calkins H , Chen SA , Davies W , Iesaka Y , Kalman J et al. 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Fassini, Gaetano, Conti, Sergio, Moltrasio, Massimo, Maltagliati, Anna, Tundo, Fabrizio, Riva, Stefania, Dello Russo, Antonio, Casella, Michela, Majocchi, Benedetta, Zucchetti, Martina, Russo, Eleonora, Marino, Vittoria, Pepi, Mauro, Tondo, Claudio. Concomitant cryoballoon ablation and percutaneous closure of left atrial appendage in patients with atrial fibrillation, EP Europace, 2016, 1705-1710, DOI: 10.1093/europace/euw007